Viral infections are a major cause of lost productivity among workers and can result in discomfort, illness, and even death. Some viruses are transmitted readily among individuals, with infections rates among local populations sometimes reaching sixty to eighty percent. Outbreaks of influenza virus infection in particular have reached epidemic and pandemic proportions.
Unlike the vast array of drugs available to treat bacterial infections, the number of agents effective in treating viral infections is quite limited. Because the vital life cycle is intimately involved with host cell metabolism, selective toxicity against viruses is difficult to achieve. Viruses that mutate readily into resistant strains limit the effectiveness of potential therapeutic agents.
The initial step in influenza virus infection is the attachment of the virus to various cell receptors. The ability to prevent attachment would provide a means by which viral infection could be prevented or its spread halted.
Attachment is mediated by the trimeric vital envelope glycoprotein hemagglutinin, which recognizes and binds sialic acid residues on host cell glycoproteins or glycolipids. Because sialic acid residues are found on a great many cell surface macromolecules, viral hemagglutinin binds a wide range of host cell receptors. A hemagglutinin receptor, therefore, is any host cell molecule containing a site that hemagglutinin will recognize and bind, with the major determinant for recognition being presence of a terminal sialic acid or neuraminic acid residue.
Competing with hemagglutinin for receptors is neuraminidase, a second vital envelope glycoprotein which binds and cleaves terminal sialic acid residues from host cell surface molecules. Cleavage of the terminal sialic acid residue by neuraminidase removes the site of hemagglutinin recognition and thereby prevents infection by the virus.
Hemagglutination and viral infection can be inhibited by soluble receptor analogs. These analogs can include the soluble portions of sialic acid-containing host cell surface macromolecules or even smaller portions thereof. Some low molecular mass sialic acid derivatives have been tested, but inhibitory activity is low. It has been shown that the .alpha.-benzyl glycoside of 5-acetyl neuraminic acid shows greater inhibition of attachment than 5-acetyl neuraminic acid itself. Inhibitory activity is decreased by neuraminidase cleavage of these receptor analogs, which effectively lowers the concentration of the analog with respect to hemagglutinin. The .alpha.-benzyl derivative of neuraminic acid is not immune to this cleavage.
Ideally, a viral attachment inhibitor should have the following properties:
1. The inhibitor should bind with hemagglutinin more tightly than with neuraminidase. PA0 2. It should not be broken down or should be broken down only slowly by neuraminidase so that the analog will remain in the organism; PA0 3. It should bind with the maximum possible number of virus strains.
Hemagglutinin recognizes sialic acids, a group of acidic sugars that includes N-acetyl neuraminic acid. Analogs of this compound have been synthesized. To be an effective attachment inhibitor, a synthetic analog should contain all of the elements of natural sialic acid that are required for hemagglutinin binding: a carboxyl group, a glycerol residue, and an acetamido group. Ideally, a virus attachment inhibitor should closely resemble the binding site of hemagglutinin, which exists on the surface of viruses as a trimer.
It has been known in the art that virus-cell interaction is multivalent and cooperative. Polyvalent receptor analogs, such as proteins conjugated with the sialic acid N-acetyl neuraminic acid, have been shown to be active in inhibiting hemagglutination. Attachment of sialic acids alone to a carrier does not afford resistance to neuraminidase cleavage, and as a result these multivalent receptor analogs would not be effective for extended prevention of viral infection.
The invention described herein relates to a synthetic analog of neuraminic acid that inhibits viral attachment and is resistant to cleavage by neuraminidase. The compounds described herein are useful in prophylaxis and early treatment of infection by multiple strains of influenza virus. Further, this synthetic analog being attached to a polymer yields a multivalent virus attachment inhibitor of increased inhibitory activity.